This new application is to request for five years support to pursue a novel mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs) in Alzheimer's disease (AD), the most common form of age- related dementing illness. Increasing evidence suggests that NSAIDs have beneficial effects in the treatment or prevention of AD. The mechanisms of NSAID action in AD are unknown although it is widely believed that their anti-inflammatory properties and cyclo-oxygenase (COX) inhibition account for their beneficial effects. Our working hypothesis states that certain NSAIDs are useful in AD therapy by selectively reducing the levels of the pathogenic 42 amino acid species of amyloid beta-peptide (Abeta42) in brain through a cyclo-oxygenase (COX) independent mechanism. In preliminary studies, we found that several NSAIDs reduced the levels of Abeta42 in medium or cultured cells at concentrations above that required for COX inhibition. However, this property was not shared by all NSAIDs, including the newer COX-2 selective inhibitors. Indeed, NSAIDs were able to reduce Abeta42 levels in cell deficient in COX-2 and COX-2 by targeted gene deletions. Importantly, the in vitro results have been confirmed in short term studies of NSAIDs in transgenic mice, thereby demonstrating the physiological relevance of the tissue cultured funding in vivo. Therefore, we hypothesize that Abeta42 reduction and anti-inflammatory effects are parallel mechanisms that together contribute to the apparent efficacy of NSAIDs in AD. The program will rigorously test this hypothesis through three Projects: 1) define the cellular mechanisms that underlie Abeta42 reduction by NSAIDs, 2) identify compounds that maximize the Abeta42 reducing property and test these and existing NSAIDs in vivo, and 3) characterize these Abeta42 lowering effects in human subjects.